The present invention relates to a convenient process for the preparation of optically pure 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid and its derivatives. More specifically, the invention pertains to a method for producing optically pure 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid and its derivatives through the reaction of optically pure phenylalanine and its derivatives with a formaldehyde precursor, such as, for example formaline, trioxane, dialkoxymethane or paraformaldehyde in 37% concentrated hydrochloric acid followed by neutralization.
(L)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid is a non-natural amino acid useful for the synthesis of ACE inhibitor (Miyake et al. J. Takeda Res. Lab. 1984, 43, 53; Suj et al. Eur. Patent-A 39804; Arzeno et al. Eur. Patent-A 260118) and bradykinin antagonists (Henke et al. Eur. Patent-A 0370453; Hook et al. J. Pharmacol. 1991, 102, 769; J. Pharmacol. 1991, 114, 297).
In general, racemization and low yields are known to be the major drawbacks of Pictet-Spengler cyclization for the synthesis of optically pure 1,2,3,4-tetrahydro-3isoquinolinecarboxylic acid from optically pure phenylalanine (Julian et al. J. Am. Chem. Soc. 1948, 70, 182; Archer J. Org. Chem 1961, 16, 430; Hein et al. J. Am. Chem Soc. 1962, 84, 4487; Shinkai et al. J. Med. Chem. 1988, 31, 2092).
Recently, Soeda et al. (JP 02193969) reported that (L)-1,2,3,4-tetrahydro-3isoquinolinecarboxylic acid hydrochloric acid salt of optical purity 59.7-85.4% e.e. was obtained in 45.6-85.4% yields from the reaction of optically pure (L)-phenylalanine with paraformaldehyde in concentrated hydrochloric acid. However, this process is inefficient in the view of the low yields and the low optical purities of the product.
Kuge et al. reported that (L)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid hydrobromic acid salt of optical purity 97% e.e. was obtained in 87.4% yield from the reaction of (L)-phenylalanine with formaldehyde or paraformaldehyde in 37% concentrated hydrobromic acid. However, this process has the disadvantages in the cost and the waste treatment of hydrobromic acid. Moreover, the effect of the repetitive use of hydrochloric acid, hydrobromic acid and other inorganic acids or organic acids have not as yet been reported.
In order to overcome these disadvantages, it would be desirable to provide an efficient process for the preparation of 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid of high optical purity using hydrochloric acid which is economical to use and provides for ease of waste treatment.